FDA Gives Updates on Newly Approved Agents for Rheumatic Diseases

“We have had another busy year at the agency,” said Erick J. Gapud, MD, PhD, Clinical Team Leader for the Division of Rheumatology and Transplant Medicine (DRTM) at the U.S. Food and Drug Administration (FDA). “We approved new indications for both adult and pediatric rheumatology as well as new biosimilars and interchangeables in the rheumatology space.”

Dr. Gapud opened the annual Update and Safety Issues on Recently Approved Agents for Rheumatic Diseases on Saturday, Nov. 16, with a review of new approvals. Other topics included newly identified safety issues and the role of artificial intelligence (AI) in FDA submissions. The session will be available on-demand to all registered ACR Convergence 2024 participants after the meeting through Oct. 10, 2025, by logging into the meeting website.

New adult approvals for the year included benralizumab for eosinophilic granulomatosis with polyangiitis (EGPA), and bimekizumab-bkzx for psoriatic arthritis (PsA), ankylosing spondylitis (AS), and non-radiographic axial spondyloarthropathy (nr-axSpA).

Benralizumab is an interleukin-5 (IL-5) receptor monoclonal antibody previously approved for add-on maintenance for adults and children 6 years or older with severe asthma, eosinophilic phenotype. The new approval for adults with EGPA is based on a single randomized controlled noninferiority trial versus mepolizumab.

All the familiar safety precautions continue to apply to the new indication, Dr. Gapud said. Additional safety considerations include headache, pyrexia, and pharyngitis.

Bimekizumab-bkzx is an interleukin-17 (IL-17) A/F antagonist previously approved for moderate to severe plaque psoriasis (Pso). The new indications include adults with active PsA, nr-axSpA with objective signs of inflammation, and active AS.

Approvals were based on two randomized controlled trials in biological disease-modifying antirheumatic drugs (DMARDs) naïve and anti-tumor necrosis factor alpha (TNFα) experienced patients. In nr-axSpA, bimekizumab showed a 42.3% improvement versus placebo in ASAS 20 response and 37.5% in ASAS 40 response. In AS, bimekizumab showed a 34.0% improvement versus placebo in ASAS 30 response and 32.4% in ASAS 40 response.

Additional safety issues included headache, injection site reaction, gastroenteritis, and fatigue.

New pediatric approvals for polyarticular juvenile idiopathic arthritis (pJIA) include certolizumab pegol, sarilumab, and upadacitinib. All were approved based on pharmacokinetic (PK) extrapolation from adult rheumatoid arthritis (RA), adult PsA, and pediatric PsA.

Belimumab subcutaneous auto injector was approved for systemic lupus erythematosus (SLE) in pediatric patients 5 years or older. Approval was based on PK extrapolation from adults with SLE and children with SLE treated using intravenous belimumab.

Tocilizumab biosimilar approvals included tociluzumab-aazg, the first tocilizumab biosimilar with subcutaneous form, and tocilizumab-bavi for giant cell arteritis (GCA) and COVID-19.

Adalimumab biosimilar approvals included adalimumab-aacf and adalimumab-adbm high-concentration formulation.

There were also two adalimumab interchangeable approvals: adalimumab-ryvk, the first high-concentration adalimumab interchangeable, and adalimumab-bwwd prefilled syringe (PFS).

One etanercept biosimilar was approved, etanercept-ykro auto injector, as well as one interchangeable, etanercept-ykro PFS.

New safety issues

Drug reaction with eosinophilia and systemic symptoms (DRESS) led the discussion of safety issues the FDA has addressed in the past year.

DRESS is a severe, potentially life-threatening, delayed drug reaction with mortality up to 10% that can take weeks to months to onset, said Amit Golding, MD, PhD, DRTM Clinical Team Leader. Skin manifestations are often the first clue to diagnosis with macropapular eruptions that may progress to a coalescing erythema.

Other manifestations may include fever, lymphadenopathy, hematologic abnormalities, and/or internal organ involvement and injury. Cutaneous and visceral involvement generally resolves gradually after drug withdrawal.

Multiple observations and trials have confirmed the risk of DRESS in a minority of patients taking interleukin-1 (IL-1)/interleukin-6 (IL-6) inhibitors tocilizumab, anakinra, or canakinumab. Labeling for all three now includes a warning for DRESS.

Post-marketing studies have linked two IL-17 inhibitors, secukinumab and ixekizumab, to serious opportunistic infections, including cryptococcal meningitis and hepatitis B reactivation. Label warnings for both agents have been updated.

Hypocalcemia is now a recognized risk for denosumab in patients with advanced kidney disease based on studies using Centers for Medicare and Medicaid Services patient data. The drug now carries a black box warning for severe hypocalcemia in patients with advanced kidney disease.

Kaposi’s sarcoma (KS) has been added to warnings for corticosteroids. The new warning is based on multiple published case reports of KS in patients receiving corticosteroids, usually for chronic conditions. Corticosteroids appear to activate human herpesvirus-8, which causes KS.

Labels for avacopan and voclosporin have new warnings for drug-drug interaction with 40 mg simvastatin. The new warning recommends reducing simvastatin doses to 10 mg or 20 mg daily and consideration of reducing other CYP3A4 substrates concurrently with avacopan or voclosporin.

Updated findings from pregnancy registries have been added to tofacitinib and tocilizumab labeling. Registry data does not implicate either agent in major birth defects, miscarriages, or other adverse maternal/fetal outcomes, Dr. Golding reported.

Both agents are present in human milk and there are no reported adverse effects from breastfeeding, although data on breastfeeding is limited to a small number of cases.

AI in FDA submissions

AI use in FDA submissions has mushroomed from just one submission in 2016 to 128 in 2021.

“We have seen an increasing use of AI across the entire spectrum of drug discovery and development,” said Austin Anderson, MD, DRTM Medical Officer. “The numbers of submissions with AI elements continue to increase.”

Dr. Anderson said the FDA sees potential for AI in all phases, from drug target discovery to post-market surveillance. COVID-19 pushed the agency to incorporate different uses of AI in approvals for both baricitinib and anakinra.

The agency has developed a unified approach to AI in regulatory submissions, as outlined in Artificial Intelligence & Medical Products, published in March 2024. The FDA expects to focus on encouraging collaboration between stakeholders, creating harmonized standards, developing new regulatory approaches, and supporting research on the evaluation and monitoring of AI performance.

Next steps for the FDA include:

• more clarity in regulatory approaches to submissions with AI elements;
• guidance on the use of AI and machine learning in submissions (in process);
• continuing a risk-based approach to regulation;
• continuing to engage parties across the AI ecosystem, including academia, industry, and international regulators.